Medicinal aerosols and methods of delivery thereof

ABSTRACT

The replacement of chlorofluorohydrocarbon propellants in medical aerosols is of the utmost importance to the pharmaceutical industry. A number of formulations have been investigated. 
     The present invention provides a medical aerosol formulation comprising a particular medicament, a fluorocarbon propellant and 6 to 25% w/w of the total formulation of a polar co-solvent, such formulation being substantially free of surfactant. Canisters suitable for delivering such a pharmaceutical formulation are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/999,752, filed on Jun. 4, 1997, the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical formulations for inhalationaerosols. The Montreal Protocol on ozone depleting gases has made thereformulation of existing pharmaceutical aerosols. for inhalationtreatment containing chlorofluorohydrocarbon propellants, a matter ofurgency for the pharmaceutical industry.

DETAILED DESCRIPTION

A number of hydrofluorocarbons (HFCs) have been the subject totoxicological testing and two in particular P134a(1,1,1,2-tetrafluoroethane) and P227 (1,1,1,2,3,3,3-heptafluoropropane)have been identified as safe for use in pharmaceutical aerosols.

A number of patent applications have been submitted in this field, thefirst being EP 372777, which discloses the use of four componentmixtures, comprising a medicament, a surfactant, P134a and a co-solventof higher polarity than the P134a, in the form of a solution or asuspension.

As inhalation aerosols are meant for administration to the lung, it haslong been accepted that such formulations should contain as fewingredients as possible, to avoid putting unnecessary materials into thelung.

Historically, despite EP 372777, solution aerosols contained onlymedicament, propellant or propellant mixtures and, if necessary,co-solvent, usually ethanol, eg U.S. Pat. No. 2,868,691. The use of asurfactant was normally unnecessary for solution aerosols. However,historically medicinal suspension aerosols have contained a surfactanteg U.S. Pat. No. 3,014,844, as it was considered that the use of asurfactant was necessary to prevent agglomeration of particles, toprevent adhesion to the sides of the canister, and to aid valvelubrication and prevent valve sticking.

However it was disclosed in EP 616525 that it is possible to preparemedicament suspensions in a hydrofluorocarbon without the need for asurfactant, if a polar co-solvent was added. The normal co-solventethanol, has well established physiological actions and being a pureabsorbable liquid eliminates any possibility of residues remaining inthe lung. Irritation or possible toxicity from the surfactant, many ofwhich are mixtures of similar compounds, are avoided.

EP 616525 specifically limits the polar co-solvent level to 0.01 to 5%w/w and in particular states (page 3, line 55) that the preferred levelis about 0.1% w/w.

According to a first aspect of the present invention there is provided amedicinal aerosol formulation comprising a particulate medicament, afluorocarbon propellant and 6%s to 25% w/w of the total formulation of apolar co-solvent, such formulation being substantially free ofsurfactant.

According to a second aspect of the present invention there is provideda medicinal aerosol formulation, comprising one or more particulatemedicaments, one or more fluorocarbon or hydrocarbon or aliphatic gaspropellants and 6% to 25% w/w of a polar co-solvent.

According to a third aspect of the present invention there is provided acanister suitable for delivering a pharmaceutical aerosol formulation,which comprises a container capable of withstanding the vapor pressureof the propellant used, which container is closed with a metering valveand contains a pharmaceutical aerosol formulation which comprisesparticulate medicament, a propellant consisting all or part offluorocarbon and 6% to 25% of a polar co-solvent, which is substantiallyfree of surfactant.

It has now been surprisingly found that higher levels of alcohol havebeneficial results. Levels of 6% or more of ethanol produce satisfactorysuspensions, which do not agglomerate on standing, and on reshakingproduce finely dispersed medicament. It is believed that the higherlevels of alcohol reduce the degree of deposition on the inside of thecan. This is a very desirable feature. In addition, the use of theselarger percentages of ethanol enables a much cheaper production process.

Medicinal aerosols can be filled either with one dose of liquidcontaining all of the ingredients mixed together or by a two doseprocess where the first dose contains the medicament and all otheringredients, including co-solvents, surfactants, if any, ancillarycompounds eg flavors, if any, and some times some of the propellantfollowed by a second dose of pure propellant. This two dose fill hasmajor cost advantages in that the volume of mix for a fixed number ofcans is significantly smaller enabling the use of smaller mixingvessels. In particular, with the use of the new HFC propellants, whichhave lower boiling points than the old CFC propellants, the use of a onedose fill may involve the use of cooled pressurized vessels to preventevaporation of the propellant gas during mixing and filling. With thenew formulations with added extra co-solvent a first mix of justmedicament suspended in the co-solvent can be used, followed by a seconddose of pure propellant. This means that the propellant can be doseddirectly from a holding tank into the can without any need to mix andstore with the other ingredients. For example a mix weight of 1 g ofmedicament and co-solvent can be followed by 7.5 g of propellant. Inthis way the volume to be mixed is reduced from 8.5 g to 1 g. All theexamples in EP 616525 are of laboratory scale, where the handlingproblems are much easier, but all the formulations described are suchthat it would not be practicable to fill in two doses without mixing thepropellant, as is the case with the present disclosure.

The description of the filling method given on page 5 lines 2-13indicates that only a one dose filling method is envisaged.

In all cases of the present invention the medicament consists of aparticle size suitable for inhalation into the lung and will thus beless than 100 microns, desirably less than 20 microns and preferably inthe range of 1-10 microns, normally with a mean particle size 1-5microns.

Medicaments which may be administered in aerosol formulations accordingto the invention include any drug useful in inhalation therapy which maybe presented in a form which is substantially completely insoluble inthe selected propellant.

Appropriate medicaments may thus be selected from, for example,analgesics, eg codeine, dihydromophine, ergotamine, fentanyl ormorphine; anginal preparations, eg diltiazem; antiallergics, egcromoglycate, ketotifen or nedocromil; anti-infectives, egcephalosporins, penicillins, streptomycin, sulphonamides, tetracyclinesand pentamidine; antihistamines, eg methapyrilene; anti-inflammatories,eg beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, eg noscapine; bronchodilators,eg ephedrine, adrenaline, fenoterol, formoterol, isoprenaline,metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol,reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine,tolubuterol, orciprenaline; diuretics, eg amiloride; anticholinergics,eg ipratropium, atropine or oxitropium; hormones, eg cortisone,hydrocortisone or prednisolone; xanthines, eg aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; and therapeuticproteins and peptides, eg insulin or glucagon. It will be clear to aperson skilled in the art that, where appropriate, the medicaments maybe used in the form of salts (eg as alkali metal or amine salts or asacid addition salts) or as esters (eg lower alkyl esters) or as solvates(eg hydrates) to optimize the activity and/or stability of themedicament and/or to minimize the solubility of the medicament in thepropellant.

Preferred are those compounds which are also substantially insoluble inthe co-solvent. Particularly preferred as medicament is salbutamoleither as base or as a salt and especially salbutamol sulphate.

Co-solvents may be selected from polar alcohols and polyols,particularly C2-C6 aliphatic alcohols and polyols, such as propyleneglycol, and preferably ethanol. Levels of co-solvent will be between 6%and 25% w/w of the total canister content, preferably between 10-15% w/wof canister content.

The propellant may be a hydrofluorocarbon, particularly P134a or P227.Other hydrofluorocarbons or hydrocarbons or aliphatic gases (egDimethylether) may be added to modify the propellant characteristics asrequired.

The product is preferentially produced by weighing the active medicamentand suspending it in the co-solvent. The appropriate amount ofsuspension is then dosed into the can, followed by a second dose ofpropellant or propellant mix. However, a one shot fill or any otherequivalent method may be employed.

The normal medicinal product on the market has an actuator with sprayorifice diameter of about 480 microns. However, with the largerpercentages of ethanol envisaged in this invention, it is desirable thatthe co-solvent evaporates from the particles as rapidly as possible.

This is achieved by reducing the aperture to between 100-300 microns,which for the same dosage or drug, gives more rapid evaporation of theco-solvent. A particularly preferred embodiment of the invention is acombination of a level 10-15% co-solvent (normally ethanol) with a stemaperture of 150-250 microns.

The invention is further described by means of example but not in anylimitative sense.

EXAMPLE

Salbutamol Sulphate 0.03 g Ethanol 0.97 g Tetrafluoroethane (P134a)  7.5g

The salbutamol sulphate previously micronized to give over 90% ofparticles below 10 microns was weighed out and added to the ethanol. Thesuspension was mixed until is was smooth and uniform and then filledinto the aerosol canister. The metering valve assembly was crimped(preferably vacuum crimped) on the canister and then the P134a wasfilled through the valve. The valve capacity is such as to deliver 100micrograms of salbutamol, as salbutamol sulphate per actuation.

A particularly preferred use of such a canister is in a patient breathoperated device rather than the normal hand operated device. Suchdevices are available commercially such as those under the trade mark“Easi-Breathe”.

The invention claimed is:
 1. A product suitable for delivering apharmaceutical aerosol formulation comprising, (a) an aerosol canistercomprising a container closed with a metering valve, said containercomprising a pharmaceutical suspension aerosol formulation substantiallyfree of surfactant, and which comprises salbutamol sulphate, ethanol inan amount of 10% w/w to 15% w/w, and 1,1,1,2-tetrafluoroethane, whereinsalbutamol sulphate is substantially completely insoluble in the1,1,1,2-tetrafluoroethane, and (b) an actuator with a spray orificeaperture of from 100 to 300 microns.
 2. The product of claim 1, whereinthe aerosol formulation contains ethanol in the amount of 11.4% w/w. 3.The product of claim 1, wherein the aerosol formulation contains1,1,1,2tetrafluoroethane in the amount of 88.2% w/w.
 4. The product ofclaim 1, wherein the aerosol formulation contains salbutamol sulphate inthe amount of 0.4% w/w, ethanol in the amount of 11.4% w/w, and1,1,1,2-tetrafluoroethane in the amount of 88.2% w/w.
 5. The product ofclaim 1, wherein the spray orifice aperture is from 150 to 250 microns.6. The product of claim 5, wherein ethanol is present in the amount of10% w/w to 15% w/w.